1. Field of the Invention
The present invention relates to compositions and methods for treating cancer. In particular, the invention describes the use of a prolactin receptor antagonist in combination with an agent that inactivates the HER2/neu signaling pathway.
2. Background of the Invention
Breast cancer is the second leading cause of cancer death in women in Western society. While the cause of breast cancer is still not clear, it is generally believed that tumorigenesis is not triggered by a single etiologic agent. Instead, the genesis of breast cancer is a result of accumulated damage to cells within the breast over many years.
For decades, the primary therapies for women with breast cancer have been surgery, radiation, or a combination of the two (Miller and Langdon, BIOLOGY OF FEMALE CANCERS, CRC Press LLC, pp 43-60 (1997); Forrest, BIOLOGY OF FEMALE CANCERS, CRC Press LLC, pp 31-42 (1997)). Hormone therapy and chemotherapy are common treatments for breast cancer. But because of the heterogeneous nature of the cancer, there is a low response rate to many therapies. For example, approximately half of the cancers in the breast are estrogen receptor (ER) negative and therefore will not respond to tamoxifen (Forrest, supra).
Recently, novel agents have been designed to target oncogene products such as HER2. HER2 is located on chromosome band 17821.1 and encodes a transmembrane receptor tyrosine kinase (Ross et al., ENCYCLOPEDIC REFERENCE OF CANCER, pp. 401-3, Springer, 2001). The name HER2 is derived from Human Epidermal growth factor Receptor” as it features substantial homology with EGFR (id.). Heterodimerization of HER2 with other ErbB family members is initiated through ligand binding, and leads to autophosphorylation, transphosphorylation, and finally activation of a receptor dimer that acts as a kinase for cytoplasmic substrates (Stern, D F, Breast Cancer Res. 2:176-83 (2000).
Overexpression of the HER2 protein occurs in 25% to 30% of human breast cancers and leads to a particularly aggressive form of the disease (Ciardiello et al., Clin. Cancer Res. 7:2958-70 (2001); Miles D W, Breast Cancer Res., 3:380-84 (2001); Shawver et al., Cancer Cell, 1:117-123 (2002); Vogel et al., J. Clin. Oncol., 20:719-26 (2002)). Women whose cancer overexpresses HER2 have a poor prognosis, with a median survival of 3 years (compared to 6-7 years in HER-2 negative cases) (Slamon et al., Science 235:177-82 (1987); Chazin et al., Oncogene, 7:1859-66 (1992)). Thus, HER2 became an important target in developing chemotherapeutic agents.
HERCEPTIN® (Trastuzamab; Genentech, San Francisco, Calif.) is a humanized monoclonal antibody directed to the HER2 ectodomain and is believed to block and neutralize HER2 protein (Fendly et al., Cancer Res. 50:1550-58 (1990)). HERCEPTIN® (trastuzamab) was approved in 1998 for clinical use in HER2 overexpressing metastatic breast cancer. Recent data indicated that HERCEPTIN® (trastuzamab) has anti-tumor activity as a single agent used in a phase II clinical trial of heavily pre-treated patients with advanced breast cancer. In addition, use of HERCEPTIN® (trastuzamab) in conjunction with chemotherapy was associated with higher response rates, longer time to progression and improved survival when compared with chemotherapy alone. But despite encouraging clinical data, the overall response rate for HERCEPTIN® (trastuzamab) as a single agent is 20 to 30% (Miles; Vogel; Slamon, supra).
Therefore, there exists a need in the art to identify compositions and methods to effectively treat various cancers, including breast cancer. The present invention describes compounds that act synergistically with HERCEPTIN® (trastuzamab) to treat breast and other cancers.